Rapid Relief of Breathlessness With Fast-Acting Opioids and Benzodiazepines: A Systematic Review.

Abstract

Breathlessness can peak within minutes. Centrally acting drugs are used for rapid relief, but evidence is unclear. To assess the effectiveness and safety of fast-acting drugs affecting the central nervous system for spontaneous breathlessness with outcomes measured ≤20 minutes post-treatment. A systematic review with narrative synthesis. Searches included CENTRAL, MEDLINE (Ovid), and Embase (Ovid) up to September 2025, reference screening and trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform). We included randomized controlled trials (RCTs) in adults with advanced or severe acute disease testing opioids, benzodiazepines, antipsychotics, or cannabinoids. Eleven trials (n = 334) contributed 15 comparisons; 13 compared an opioid with placebo or another opioid; mostly small crossover trials, varying in route, dose, and setting. No trial investigated antipsychotics or cannabinoids. Two small trials showed a relevant benefit over placebo: intravenous morphine (mean difference -1.8 cm; 95% CI -3.0 to -0.6) and subcutaneous morphine (-1.1 cm; -1.9 to -0.3; high risk of bias). Trials of inhaled opioids, intranasal fentanyl, and oral hydromorphone showed no benefit compared to placebo. Midazolam was evaluated in two trials; neither showed a benefit compared to placebo or morphine; both had important methodological limitations. Adverse-event monitoring was limited. In two acute-care morphine trials, serious adverse events were more frequent in the morphine arms. Instead of use as routine care, fast-acting opioids (morphine subcutaneous or intravenous) should be considered as a second step if non pharmacological measures have failed. Further research is needed, especially for other centrally acting drugs and adverse effects.